Thimerosal is certainly a very potent neurotoxin. It should never have
been used in vaccines, particularly for infants and children. But what about
aluminum INJECTED into the body not as a vaccine preservative but as a
vaccine adjuvant? (Aluminum is not readily absorbed from the GI tract.)
Aluminum, also is a neurotoxin. This has been known for over 100 years. And
what safety studies have ever been done about the possible neurotoxic
interaction/synergism of thimerosal and aluminum?

Division of Bacteriology, National Institute for Biological Standards
and Control, Herts., UK.

Aluminum is widely used as an adjuvant in human vaccines, and children
can often receive up to 3.75 mg of parenteral aluminum during the first six
months of life. We show that intraperitoneal injection of aluminum adsorbed
vaccines into mice causes a transient rise in brain tissue aluminum levels
peaking around the second and third day after injection. This rise is not
seen in the saline control group of animals or with vaccine not containing
aluminum. It is likely that aluminum is transported to the brain by the
iron-binding protein transferrin and enters the brain via specific
transferrin receptors. PMID: 1608913, UI: 92302160

Adverse reactions after injection of adsorbed
diphtheria-pertussis-tetanus (DPT) vaccine are not due only to pertussis
organisms or pertussis components in the vaccine.

Vaccine. 1991 Oct;9(10):699-702. Review.PMID: 1759487; UI: 92101590

Aluminum compounds such as aluminum phosphate and aluminum hydroxide
are the most commonly used adjuvants with vaccines for human use. Due to the
increasing concern about the toxicity of aluminum, other adjuvants like
calcium phosphate may be evaluated as an alternative to aluminum adjuvants.
To minimize reactions after immunization with DPT vaccine due to impurities
in the toxoids, the use of toxoided purified toxins is suggested.

Neurotoxicology of the brain barrier system: new implications.

Zheng W.

J Toxicol Clin Toxicol. 2001;39(7):711-9.

College of Physicians and Surgeons, Columbia University, New York, New
York 10032, USA. wz18@columbia.edu

The concept of a barrier system in the brain has existed for nearly a
century. The barrier that separates the blood from the cerebral interstitial
fluid is defined as the blood-brain barrier, while the one that discontinues
the circulation between the blood and cerebrospinal fluid is named the
blood-cerebrospinal fluid barrier. Evidence in the past decades suggests
that brain barriers are subject to toxic insults from neurotoxic chemicals
circulating in blood. The aging process and some disease states render
barriers more vulnerable to insults arising inside and outside the barriers.
The implication of brain barriers in certain neurodegenerative diseases is
compelling, although the contribution of chemical-induced barrier
dysfunction in the etiology of any of these disorders remains poorly
understood. This review examines what is currently understood about brain
barrier systems in central nervous system disorders by focusing on
chemical-induced neurotoxicities including those associated with
nitrobenzenes, N-methyl-D-aspartate, cyclosporin A, pyridostigmine bromide,
aluminum, lead, manganese, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and
3-nitropropionic acid. Contemporary research questions arising from this
growing understanding show enormous promises for brain researchers,
toxicologists, and clinicians.

Several neurotoxic compounds, including Al, NO, and beta-amyloid may
contribute to the impairment or loss of brain cholinergic neurons in the
course of various neurodegenerative diseases. Genotype and phenotypic
modifications of cholinergic neurons may determine their variable functional
competency and susceptibility to reported neurotoxic insults. Hybrid,
immortalized SN56 cholinergic cells from mouse septum may serve as a model
for in vitro cholinotoxicity studies. Differentiation by various
combinations of cAMP, retinoic acid, and nerve growth factor may provide
cells of different morphologic maturity as well as activities of
acetylcholine and acetyl-CoA metabolism. In general, differentiated cells
appear to be more susceptible to neurotoxic signals than the
non-differentiated ones, as evidenced by loss of sprouting and connectivity,
decreases in choline acetyltransferase and pyruvate dehydrogenase
activities, disturbances in acetyl-CoA compartmentation and metabolism,
insufficient or excessive acetylcholine release, as well as increased
expression of apoptosis markers. Each neurotoxin impaired both acetylcholine
and acetyl-CoA metabolism of these cells. Activation of p75 or trkA
receptors made either acetyl-CoA or cholinergic metabolism more susceptible
to neurotoxic influences, respectively. Neurotoxins aggravated detrimental
effects of each other, particularly in differentiated cells. Thus brain
cholinergic neurons might display a differential susceptibility to Al and
other neurotoxins depending on their genotype or phenotype-dependent
variability of the cholinergic and acetyl-CoA metabolism.

Copyright 2001 Wiley-Liss, Inc.

Aluminium impairs the glutamate-nitric oxide-cGMP pathway in cultured
neurons and in rat brain in vivo: molecular mechanisms and implications for
neuropathology.

Aluminium (Al) is a neurotoxicant and appears as a possible
etiological factor in Alzheimer's disease and other neurological disorders.
The mechanisms of Al neurotoxicity are presently unclear but evidence has
emerged suggesting that Al accumulation in the brain can alter neuronal
signal transduction pathways associated with glutamate receptors. In
cerebellar neurons in culture, long term-exposure to Al added 'in vitro'
impaired the glutamate-nitric oxide (NO)-cyclic GMP (cGMP) pathway, reducing
glutamate-induced activation of NO synthase and NO-induced activation of the
cGMP generating enzyme, guanylate cyclase. Prenatal exposure to Al also
affected strongly the function of the glutamate-NO-cGMP pathway. In cultured
neurons from rats prenatally exposed to Al, we found reduced content of NO
synthase and of guanylate cyclase, and a dramatic decrease in the ability of
glutamate to increase cGMP formation. Activation of the glutamate-NO-cGMP
pathway was also strongly impaired in cerebellum of rats chronically treated
with Al, as assessed by in vivo brain microdialysis in freely moving rats.
These findings suggest that the impairment of the Glu-NO-cGMP pathway in the
brain may be responsible for some of the neurological alterations induced by
Al.

Effects of aluminium exposure on brain glutamate and GABA systems: an
experimental study in rats.

It has been postulated that the neurotoxic effects of aluminium could
be mediated through glutamate, an excitatory amino acid. Hence the effects
of aluminium administration (at a dose of 4.2mg/kg body weight daily as
aluminium chloride, hexahydrate, intraperitoneally, for 4 weeks) on
glutamate and gamma-amino butyrate (GABA), an inhibitory amino acid, and
related enzyme activities in different regions of the brain were studied in
albino rats. The glutamate level increased significantly in the cerebrum,
thalamic area, midbrain-hippocampal region and cerebellum in response to in
vivo aluminium exposure. The aluminium insult also caused significant
increases in glutamate alpha-decarboxylase activity in all the brain
regions. However, on aluminium insult, the GABA content was not
significantly changed except in the thalamic area, where it was elevated. On
the contrary, the GABA-T activities of all the regions were reduced
significantly in all regions except the midbrain-hippocampal region.
However, the succinic semi-aldehyde content of all brain regions increased,
often significantly. The aluminium-induced modification of the enzyme
activities may be either due to the direct impact of aluminium or due to
aluminium-induced changes in the cellular environment. The aluminium-induced
differential regional accumulation of glutamate or other alterations in
enzymes of the glutamate-GABA system may be one of the causes of
aluminium-induced neurotoxicity.

Dementia in patients undergoing long-term dialysis has not been
clearly defined; however, four different entities have been described.
Uraemic encephalopathy is a complication of uraemia and responds well to
dialysis. Dialysis encephalopathy syndrome, the result of acute intoxication
of aluminium caused by the use of an aluminium-containing dialysate, was a
common occurrence prior to 1980. However, using modern techniques of water
purification, such acute intoxication can now be avoided.
Dialysis-associated encephalopathy/dementia (DAE) is always associated with
elevated serum aluminium levels. Pathognomonic morphological changes in the
brain have been described, but the mechanism for the entry of aluminium into
the CNS is incompletely understood. The mechanisms involved in the
pathogenesis of the neurotoxicity associated with aluminium are numerous.
Although only a very small fraction of ingested aluminium is absorbed, the
continuous oral aluminium intake from aluminium-based phosphate binders, and
also of dietary or environmental origin, is responsible for aluminium
overload in dialysis patients. Age-related dementia, especially vascular
dementia, occurs in patients undergoing long-term dialysis as frequently as
it does in the general population. The differential diagnoses of
dialysis-associated dementias should include investigation for metabolic
encephalopathies, heavy metal or trace element intoxications, and distinct
structural neurological lesions such as subdural haematoma, normal pressure
hydrocephalus, stroke and, particularly, hypertensive encephalopathy and
multi-infarct dementia. To prevent DAE, dietary training programmes should
aim to achieve the lowest phosphate intake and pharmacological tools should
be used to keep serum phosphate levels below 2 mmol/L. To prevent vascular
dementia, lifestyle modification should be undertaken, including optimal
physical activity and fat intake, nicotine abstinence, and targeting optimal
blood glucose, cholesterol and triglyceride levels, and blood pressure, to
those outlined in current recommendations.

The toxicology of aluminum in the brain: a review.

Yokel RA.

Neurotoxicology. 2000 Oct;21(5):813-28.

College of Pharmacy and Graduate Center for Toxicology, University of
Kentucky Medical Center, Lexington, USA.
ryokel1@pop.uky.edu

Aluminum is environmentally ubiquitous, providing human exposure.
Usual human exposure is primarily dietary. The potential for significant Al
absorption from the nasal cavity and direct distribution into the brain
should be further investigated. Decreased renal function increases human
risk of Al-induced accumulation and toxicity. Brain Al entry from blood may
involve transferrin-receptor mediated endocytosis and a more rapid process
transporting small molecular weight Al species. There appears to be Al
efflux from the brain, probably as Al citrate. There is prolonged retention
of a fraction of Al that enters the brain, suggesting the potential for
accumulation with repeated exposure. Al is a neurotoxicant in animals and
humans. It has been implicated in the etiology of sporadic Alzheimer's
disease (AD) and other neurodegenerative disorders, although this is highly
controversial. This controversy has not been resolved by epidemiological
studies, as only some found a small association between increased incidence
of dementia and drinking water Al concentration. Studies of brain Al in AD
have not produced consistent findings and have not resolved the controversy.
Injections of Al to animals produce behavioral, neuropathological and
neurochemical changes that partially model AD. Aluminum has the ability to
produce neurotoxicity by many mechanisms. Excess, insoluble amyloid beta
protein (A beta) contributes to AD. Aluminum promotes formation and
accumulation of insoluble A beta and hyperphosphorylated tau. To some
extent, Al mimics the deficit of cortical cholinergic neurotransmission seen
in AD. Al increases Fe-induced oxidative injury. The toxicity of Al to
plants, aquatic life and humans may share common mechanisms, including
disruption of the inositol phosphate system and Ca regulation. Facilitation
of Fe-induced oxidative injury and disruption of basic cell processes may
mediate primary molecular mechanisms of Al-induced neurotoxicity. Avoidance
of Al exposure, when practical, seems prudent.

Medical Research Council (MRC) Dunn Nutrition Unit, Cambridge, United
Kingdom.

BACKGROUND: Aluminum, a contaminant of commercial intravenous-feeding
solutions, is potentially neurotoxic. We investigated the effect of
perinatal exposure to intravenous aluminum on the neurologic development of
infants born prematurely. METHODS: We randomly assigned 227 premature
infants with gestational ages of less than 34 weeks and birth weights of
less than 1850 g who required intravenous feeding before they could begin
enteral feeding to receive either standard or specially constituted,
aluminum-depleted intravenous-feeding solutions. The neurologic development
of the 182 surviving infants who could be tested was assessed by using the
Bayley Scales of Infant Development at 18 months of age. RESULTS: The 90
infants who received the standard feeding solutions had a mean (+/-SD)
Bayley Mental Development Index of 95+/-22, as compared with 98+/-20 for the
92 infants who received the aluminum-depleted solutions (P=0.39). In a
planned subgroup analysis of infants in whom the duration of intravenous
feeding exceeded the median and who did not have neuromotor impairment, the
mean values for the Bayley Mental Development Index for the 39 infants who
received the standard solutions and the 41 infants who received the
aluminum-depleted solutions were 92+/-20 and 102+/-17, respectively
(P=0.02). The former were significantly more likely (39 percent, vs. 17
percent of the latter group; P=0.03) to have a Mental Development Index of
less than 85, increasing their risk of subsequent educational problems. For
all 157 infants without neuromotor impairment, increasing aluminum exposure
was associated with a reduction in the Mental Development Index (P=0.03),
with an adjusted loss of one point per day of intravenous feeding for
infants receiving the standard solutions. CONCLUSIONS: In preterm infants,
prolonged intravenous feeding with solutions containing aluminum is
associated with impaired neurologic development.